Adaptation and Propagation

Fungi often develop both virulence mechanisms (e.g., capsule
and ability to grow at 37oC) and morphologic forms
(e.g., yeasts, hyphae, spherules, and sclerotic bodies) that
facilitate their multiplication within the host.

Dissemination

Dissemination of fungi in the body indicates a breach or
deficiency of host defenses (e.g., endocrinopathies and immune
disorders).

Host Factors

Healthy, immunologically-competent individuals have a high
degree of innate resistance to fungi. Resistance to fungi is
based primarily upon cutaneous and mucosal physical barriers.
Severity of disease depends on factors such as inoculum,
magnitude of tissue destruction, ability of fungus to multiply in
the tissue, and the immune status of the host.

Fungal Factors

Enzymes such as keratinase, the presence of capsule in Cryptococcus
neoformans, the ability to grow at 37°C, dimorphism, and
other as yet undefined factors contribute to fungal pathogenesis
which involves a complex interplay of many fungal and host
factors.

INTRODUCTION

Fungi are ubiquitous in nature and exist as free-living
saprobes that derive no obvious benefits from parasitizing humans
or animals. Since they are widespread in nature and are often
cultured from diseased body surfaces, it may be difficult to
assess whether a fungus found during disease is a pathogen or a
transient environmental contaminant. Before a specific fungus can
be confirmed as the cause of a disease, the same fungus must be
isolated from serial specimens and fungal elements
morphologically consistent with the isolate must be observed in
tissues taken from the lesion. In general, fungal infections and
the diseases they cause are accidental. A few fungi have
developed a commensal relationship with humans and are part of
the indigenous microbial flora (e.g., various species of Candida,
especially Candida albicans, and Malassezia furfur).
Although a great deal of information is available concerning the
molecular basis of bacterial pathogenesis, little is known about
mechanisms of fungal pathogenesis. Infection is defined as entry
into body tissues followed by multiplication of the organism. The
infection may be clinically inapparent or may result in disease
due to a cellular injury from competitive metabolism, elaboration
of toxic metabolites, replication of the fungus, or an immune
response. Immune responses may be transient or prolonged and may
be cell-mediated, humoral (with production of specific antibody
to components of the infecting organism), or both. Successful
infection may result in disease, defined as a deviation from or
interruption of the normal structure or function of body parts,
organs, or systems (or combinations thereof) that is marked by a
characteristic set of symptoms and signs and whose etiology,
pathology, and prognosis are known or unknown.

Entry

Fungi infect the body through several portals of entry (Table
74-1). The first exposure to fungi that most humans experience
occurs during birth, when they encounter the yeast C. albicans
while passing through the vaginal canal. During this process the
fungus colonizes the buccal cavity and portions of the upper and
lower gastrointestinal tract of the newborn, where it maintains a
life-long residence as a commensal.

Another fungus, Malassezia furfur, is common in areas
of skin rich in sebaceous glands. How it colonizes the skin is
not known, but both M furfur and C albicans are the
only fungi that exist as commensals of humans and are considered
part of the indigenous flora. Only under certain unusual
circumstances have they caused disease. Other fungi that have
been implicated in human diseases come from exogenous sources,
where they exist as saprobes on decaying vegetation or as plant
parasites. Fungi rarely cause disease in healthy,
immuno-competent hosts, even though we are constantly exposed to
infectious propagules. It is only when fungi accidentally
penetrate barriers such as intact skin and mucous membrane
linings, or when immunologic defects or other debilitating
conditions exist in the host, that conditions favorable for
fungal colonization and growth occur. When C albicans, for
example, is implicated in disease processes, it may indicate that
the patient has a coexisting immune, endocrine, or other
debilitating disorder. In most cases, the underlying disorder
must be corrected to effectively manage the fungal disease.

Adaptation and Propagation

Although most fungal diseases are the result of accidental
encounters with the agent, many fungi have developed mechanisms
that facilitate their multiplication within the host. For
example, the dermatophytes that colonize skin, hairs, and nails
elaborate enzymes that digest keratin. Candida albicans as
a commensal organism exists in a unicellular yeastlike
morphology, but when it invades tissues it becomes filamentous;
conversely, the systemic fungi Histoplasma capsulatum, Blastomyces
dermatitidis, and Paracoccidoides brasiliensis exist
as molds in nature and change to a unicellular morphology when
they cause disease. Other properties, such as capsule production
by C neoformans and the adherence properties of Candida
species to host tissues, also contribute to their pathogenicity.
In general, the fungi that cause systemic disease must be able to
grow and multiply at 37°C.

Dissemination

Disseminated fungal diseases usually indicate a breach in host
defenses. Such a breach may be caused by endocrinopathies or
immune disorders, or it may be induced iatrogenically. Effective
management of the fungal infection requires a concerted effort to
uncover and correct the underlying defects.

Host Factors

The high degree of innate resistance of humans to fungal
invasion is based primarily on the various protective mechanisms
that prevent fungi from entering host tissues. Fungal growth is
discouraged by the intact skin and factors such as naturally
occurring long-chain unsaturated fatty acids, pH competition with
the normal bacterial flora, epithelial turnover rate, and the
desiccated nature of the stratum corneum. Other body surfaces,
such as the respiratory tree, gastrointestinal tract, and vaginal
vault, are lined with mucous membranes (epithelium) bathed in
fluids that contain antimicrobial substances, and some of these
membranes are lined with ciliated cells that actively remove
foreign materials. Only when these protective barriers are
breached can fungi gain access to, colonize, and multiply in host
tissues. Fungi gain access to host tissues by traumatic
implantation or inhalation. The severity of disease caused by
these organisms depends upon the size of the inoculum, magnitude
of tissue destruction, the ability of the fungi to multiply in
tissues, and the immunologic status of the host.

Fungal Factors

Most of the fungi that infect humans and cause disease are
classified by tissue or organ levels that are primary sites of
colonization. These are discussed below.

Superficial Fungal Infections

Superficial fungal infections involve only the outermost
layers of the stratum corneum of the skin (Phaeoannellomyces
werneckii [syn. Exophiala werneckii] and M furfur)
or the cuticle of the hair shaft (Trichosporon beigelii
and Piedraia hortae). These infections usually constitute
cosmetic problems and rarely elicit an immune response from the
host (except occasionally M furfur infections). Recently T
beigelii and M furfur were implicated as opportunistic
agents of disease, particularly in immunosuppressed or otherwise
debilitated patients. Patients are accidentally infected with
these common organisms via indwelling catheters or intravenous
lines. Virtually nothing is known concerning the pathogenic
mechanisms of these fungi.

Dermatophyte Infections

The dermatophytes are fungi that colonize skin, hair, and
nails on the living host. These fungi possess greater invasive
properties than those causing superficial infections, but they
are limited to the keratinized tissues. They cause a wide
spectrum of diseases that range from a mild scaling disorder to
one that is generalized and highly inflammatory. Studies have
shown that the disease-producing potential of these agents
depends on various parasite and host factors, such as the species
of organism, immunologic status of the host, type of clothing
worn, and type of footwear used. Trauma plays an important role
in infection. These organisms gain entry and establish themselves
in the cornified layers of traumatized or macerated skin and its
integument and multiply by producing keratinase to metabolize the
insoluble, tough fibrous protein. The reason why these agents
spread no deeper is not known, but it has been speculated that
factors such as cell-mediated immunity and the presence of
transferrin in serum inhibit fungal propagation to the deeper
tissue layers and systemic disease does not occur. Some
dermatophytes have evolved a commensal relationship with the host
and are isolated from skin in the absence of disease. Little is
known about specific pathogenic mechanisms of the dermatophytes,
but they do not cause systemic disease.

Subcutaneous Mycoses

The fungi that have been implicated in the subcutaneous
mycoses are abundant in the environment and have a low degree of
infectivity. These organisms gain access to the subcutaneous
tissues through traumatic implantation. Again, little is known
about mechanisms of pathogenesis. Histopathologic evidence
indicates that these organisms survive in the subcutaneous tissue
layers by producing proteolytic enzymes and maintaining a
facultative microaerophilic existence because of the lowered
redox potential of the damaged tissue. In eumycotic mycetoma
there is extensive tissue damage and production of purulent
fluid, which exudes through numerous intercommunicating sinus
tracts. Microabscesses are common in chromoblastomycosis, but the
clinical manifestation of disease indicates a vigorous host
response to the organism, as seen by the intense tissue reaction
that characterizes the disease (pseudoepitheliomatous
hyperplasia).

Although most of the fungi implicated in this category of
disease exist in a hyphal morphology, the agents of
chromoblastomycosis and sporotrichosis are exceptions.
Chromoblastomycosis is caused by a group of fungi that have
several features in common. They are all darkly pigmented
(dematiaceous) and exhibit a pleomorphism consisting of two
distinct morphologies: the organism may exist in a mycelial state
or as a thick-walled spherical cell that divides by cleavage. The
latter cell morphology, called a muriform cell, sclerotic cell or
Medlar body, is the pathologic morphology seen in tissue
sections. However, transition to the sclerotic morphology may not
be a crucial requirement for pathogenesis. Several dematiaceous
fungi cause a disease called phaeohyphomycosis, which clinically
consists of a broad group of diseases characterized by the
presence of various darkly pigmented yeastlike to hyphal
elements, but not sclerotic cells, in pathologic specimens.
Alternatively, the immune reaction of the host may dictate the
morphology that the organism assumes. Again, there is no
information about mechanisms or the role of morphogenesis in the
pathogenesis of this group of fungi.

Sporotrichosis is caused by Sporothrix schenckii, which
grows as a mold in nature or when cultured at 25°C, but as
yeastlike cells when found in tissues. The clinical
manifestations of disease caused by S schenckii vary,
depending on the immune status of the patient. The classic
condition, subcutaneous lymphanigitic sporotrichosis, is
characterized by numerous nodules, abscesses, and ulcerative
lesions that develop along the lymphatics that drain the primary
site of inoculation. The disease does not extend beyond the
regional lymph nodes that drain the site of the original
infection. Alternatively, infection may result in solitary
lesions or pulmonary disease. Clinical manifestations of
pulmonary infections vary depending on the immune status of the
patient. The immunocompetent individual has a high degree of
innate resistance to disease, and when infection occurs the
organism is often a secondary colonizer of old infarcted or
healed cavities of the lungs. If the patient is
immunocompromised, dissemination can occur. There is no
information about mechanisms of pathogenesis of this dimorphic
fungus.

Systemic Mycoses

Of all the fungi that have been implicated in human disease,
only the six agents that cause the systemic mycoses have the
innate ability to cause infection and disease in humans and other
animals. The primary site of infection is the respiratory tract.
Conidia and other infectious particles are inhaled and lodge on
the mucous membrane of the respiratory tree or in the alveoli,
where they encounter macrophages and are phagocytosed. To
successfully colonize the host these organisms must be able to
survive at the elevated temperature of the body and either elude
phagocytosis, neutralize the hostility they encounter, or adapt
in a manner that will allow them to multiply.

Several factors contribute to infection and pathogenesis of
these organisms. Of the six systemic agents, five, Histoplasma
capsulatum, Blastomyces dermatitidis, Paracoccidioides
brasiliensis, Coccidioides immitis, and Penicillium
marneffei are dimorphic, changing from a mycelial to a
unicellular morphology when they invade tissues, except C
immitis that forms spherules. The change from mycelial to
yeast morphology in H. capsulatum appears critical for
pathogenicity. Several physiologic changes occur in the fungus
during the transition, which is induced by the temperature shift
to 37°C. The triggering event is a heat-related insult: the
temperature rise causes a partial uncoupling of oxidative
phosphorylation and a consequent decline in the cellular ATP
level, respiration rate, and concentrations of electron transport
components. The cells enter a period of dormancy, during which
spontaneous respiration is maintained at a decreased level. Then
there is a shift into a recovery phase, during which
transformation to yeast morphology is completed. Mycelial cells
of H capsulatum that are unable to undergo this
morphologic transition are avirulent. Similar observations have
been made when mycelia of B dermatitidis and P
brasiliensis are shifted from 25°C to 37°C, and it has been
implied that transformation to the yeast morphology is critical
for infection.

Coccidioides immitis is also dimorphic, but its
parasitic phase is a spherule. Little is known about the role of
morphologic transformation in infection and disease of this
organism. Dimorphism does not appear to play a role in C
neoformans pathogenesis since the organism is an encapsulated
yeast both at 25°C and in host tissues. The sexual phase of C
neoformans, Filobasidiella neoformans, is known, and
the organism assumes a filamentous morphology, producing small
basidiospores. It has been suggested that these propagules are
relevant in infection.

In addition to adjustment to the elevated temperature of the
host, the infectious propagules must deal with the hostile
cellular environment of the lungs. Studies with mutants of C
neoformans have shown that the acidic mucopolysaccharide
capsule is important in pathogenesis. Acapsular variants of the
yeast are either avirulent or markedly deficient in
pathogenicity. Since these mutants were obtained by mutagenesis,
it is difficult to rule out the contribution of other genetic
defects to their decreased pathogenicity. However, at the
cellular level, the capsular polysaccharide inhibits phagocytosis
of the yeast. Encapsulated C neoformans cells are highly
resistant to phagocytosis by human neutrophils, whereas acapsular
variants are effectively phagocytosed. The active component of
the capsular polysaccharide has been identified as
glucoronoxylomannan. In addition, the capsular polysaccharide is
poorly immunogenic in humans and laboratory animals, and the
glucoronoxylomannan component persists for extended periods in
the host.

In addition to the capsular polysaccharide, elaboration of
phenyl oxidase (an enzyme that catalyzes the oxidation of various
phenols to dopachrome) by C neoformans appears to be a
determinant of virulence, although the role of this enzyme in
virulence is unknown. The infectious propagules of H
capsulatum, B dermatitidis, P brasiliensis, and
C immitis are readily phagocytosed by alveolar
macrophages. To survive phagocytosis and to multiply, these fungi
must neutralize the effects of the phagocytes. The production of
reactive oxygen metabolites by phagocytic cells is an important
host defense against microorganisms. Studies have shown that the
yeast phase of H capsulatum fails to trigger release of
reaction oxygen metabolites in unprimed murine macrophages
despite extensive phagocytosis. How they avoid destruction by the
fungicidal mechanisms within lysosomes is unclear. Arthroconidia
of C immitis inhibit phagosome-lysosome fusion and survive
within normal murine peritoneal macrophages. Phagosome-lysosome
fusion takes place after H capsulatum infection, but the
yeast cells survive in the phagolysosome. It has been speculated
that the fungus neutralizes the fungicidal components of the
lysosome by a mechanism not yet elucidated.

There is very little information about mechanisms of fungal
pathogenicity, in contrast to what is known about molecular
mechanisms of bacterial pathogenesis. Fungal pathogenesis is
complex and involves the interplay of many factors. Studies to
elucidate these mechanisms are needed because of the increasing
incidence of opportunistic infections.